In patients with cutaneous T-cell lymphomas (CTCL), soluble interleukin-2 receptor serum levels (sIL-2R) were determined by ELISA technique, and natural killer cell (NK) activity, by a 4-h chromium-51 release assay. Decrease of NK activity correlated with the augmentation of serum sIL-2R. After a 4-d stimulation with interleukin 2 CTCL patients' peripheral mononuclear cells (PMC) showed an increase of cytotoxic activity similar to that in healthy donors' PMC. Normal donors' PMC demonstrated a diminished IL-2-induced cytotoxic activity in 25% CTCL serum (sIL-2R of 3000, 7330, and 10700 U/ml, respectively) compared to control serum (sIL-2R of 400, 340, and 420 U/ml, respectively). IL-2-dependent proliferation of 2-d phytohemagglutinin (PHA) blasts was lower in CTCL serum than in control serum. sIL-2R was enriched from one CTCL patient's serum by IL-2 affinity chromatography. Transfection of the Tac gene into NIH/3T3 fibroblasts resulted in the production of a recombinant sIL-2R. The presence of enriched native or recombinant sIL-2R inhibited interleukin-2-dependent generation of cytotoxic activity and PHA blast proliferation. We suggest that elevated sIL-2R levels account for diminished NK activity by neutralizing interleukin 2 in CTCL patients.

Abstract. In patients with metastatic malignant melanoma the distribution patterns of radiolabelled lymphokine-activated killer (LAK) cells were investigated. Peripheral mononuclear cells (PMC) were isolated from six patients. LAK cells were generated by culturing PMC in complete medium containing 1000 U interleukin (IL)-2/ml and labelled with indium 111 before retransfer. We obtained scans at 2.5, 24, 48 or 96 h after injection with a high resolution gamma-camera. Intravenously injected LAK cells distributed to the lungs, liver, spleen and bone marrow. External tumour detection of known lymph node and bone metastases was successful in four. It failed in one patient with a solitary lung metastasis and in another patient with subcutaneous metastases. Our results suggest that LAK cells show tumour homing, providing a direct interaction between tumour and cytotoxic cells. We conclude that PMC seem to retain their ability to migrate after IL-2 stimulation and 111in_label_ ling. This technique may be helpful for kinetics studies or external detection of metastases in patients with malignant melanoma.

The cytocidal and toxic effects of four cytotoxic drugs (CY, DDP, VCR, Ara-C) were studied using three types of ascites tumors (L 1210, JB-1, EAT) growing on three different mouse strains (B6D2F1, AKR, NMRI). There were considerable differences in the cytocidal effect of the same dose of each drug on the three tumor cell lines; 100% of the L 1210 ascites tumor-bearing animals were permanently cured by a high dose of CY (300 mg/kg) and 30% by DDP (13 mg/kg), while most of the JB-1 and all EAT-bearing mice died earlier than the untreated control mice. The sensitivity of the animals of the three mouse strains to the toxic effect of the same drug dose also differed. CY was better tolerated than DDP. Ara-C and VCR doses used in the present work were non-toxic and showed little cell killing effect. Furthermore, the present study showed that tumor-bearing mice were more sensitive to the toxic side effects of CY, DDP, and Ara-C than tumor-free animals. The growing tumor itself increased the vulnerability of normal cells to the drug.

Summary Peripheral blood mononuclear cells (PBMC) were taken by leukapheresis from a patient with melanoma skin metastases and stimulated in vitro using 1000 IU recombinant interleukin 2 (IL‐2)/ml to generate lymphokine‐activated killer cells (LAK cells). Two‐colour immunofluorescence analysis demonstrated an IL‐2‐induced up‐regulation of CD25 on natural killer cells (CD56+) as well as on T lymphocytes (CD3+). After radiolabelling with indium‐111, the cells were reinfuse. Gamma‐camera imaging revealed an enrichment at the tumour sites. Immunostaining of tumour tissue taken before and after scintigraphy demonstrated CD25+ Tlymphocytes (CD2+, CD3+), but no natural killer cells (CD16+, CD56+) infiltrating the metastases. LAK cell enrichment at melanoma metastases in vivo did not involve natural killer cells, but was characterized by increased numbers of activated T lymphocytes in this patient.

The three studies discussed show that the response of experimental ascites and solid tumors, as well as of the host organism, to a cytotoxic drug can be studied quantitatively with cell kinetic methods. Knowledge of this kind is necessary in the attempt to improve the application of cytotoxic drugs in chemotherapy of tumors which up to now has been based mainly on pure empiricism.